The objective of the proposed research is to define the regulatory mechanisms responsible for adjusting energy production to energy demands in normal myocardium and in experimentally induced heart failure. Rat hearts will be perfused using a working heart preparation which permits changes of work load to be monitored over a wide range. Rates of substrate utilization, oxygen consumption and flux through steps in the citric acid and malate-aspartate cycles will be measured during transition states of altered work load together with tissue levels of adenine nucleotides, citric acid cycle intermediates between mitochondria and cytosol will be estimated by extracting the lyophylized tissue from rapidly frozen hearts with nonpolar solvents. The relationship between extramitochondrial phosphate potential and intramitochondrial phosphate potential as a function of respiratory rate will be measured using isolated rat heart mitochondria. Isolated mitochondria will also be used to investigate the thermodynamic relationship between the adenine and guanine nucleotide systems, and the effect of physiological inhibitors on adenine nucleotide translocation. Alterations of the normal feedback regulation between energy production via mitochondrial oxidative phosphorylation and energy utilization for mechanical activity will be investigated under conditions of heart failure induced by acidosis, oxygen limitation and ischemia. Using a calcium overload model of heart failure the relationship of high calcium loading by mitochondria in situ to irreversible loss of myocardial performance will be studied. The proposed studies should provide information of relevance to the problem of the nature of the crucial factors which lead to the development of irreversible heart failure. BIBLIOGRAPHIC REFERENCES: Williamson, J. R., Gimpel, J. A., Meijer, A. J., Deleeuw, G., and Refino, C. Control of Energy Production in Cardiac Muscle: Effects of Ischemia in Acidosis. In Recent Advances in Studies on Cardiac Structure and Metabolism. University Park Press, in press, 1977. Williamson, J., Steenbergen, C., Rich, T., Deleeuw, G., Barlow, C. and Chance, B. The Nature of Ischemic Injury in Cardiac Tissue in "Pathophysiology and Therapeutics of Myocardial Ischemia" ed. by A.M. Leffer, G. J. Kelliher, M. J. Rovotto Spectrum Public., Inc. 1977.